Seminiferous Tubule Failure Research Articles

Claudin-11 and connexin-43 display altered spatial patterns of organization in men with primary seminiferous tubule failure compared with controls

To assess the spatial organization of two proteins involved in the Sertoli cell junctional complex in men with primary seminiferous tubule failure. Retrospective study. Medical research institute. Sixteen men total, six with meiotic arrest, seven with the Sertoli cell-only phenotype, and three with normal spermatogenesis. None. Differences in claudin-11 and connexin-43 organization as detected using confocal microscopy. In men with primary seminiferous tubule failure, four organizational patterns (I-IV) were recognized and quantified for claudin-11. Across these patterns, claudin-11 changed from a basal filamentous staining pattern to a punctate staining pattern with diffuse localization throughout the entire epithelium. Similar changes in staining patterns for connexin-43 were observed. Major differences were seen in the spatial organization of claudin-11 and connexin-43 in tubules from control men compared with tubules with primary seminiferous tubule failure, but we observed no differences in the spatial organization of these proteins in tubules from men with meiotic arrest and Sertoli cell-only phenotypes. The spatial organization of claudin-11 and connexin-43 is altered in men with primary seminiferous tubule failure. Disorganization of the proteins composing the Sertoli cell junctional complex may be involved in the spermatogenic impairment, possibly via loss of blood-testis barrier function.

Insulinoma Presenting with Long-Standing Depression, Primary Hypogonadism, and Sertoli Cell Only Syndrome

The aim was to report an unusual case of insulinoma presenting with long-standing depression and primary testicular failure. We describe a 34-year-old male with clinical, laboratory, and radiologic data consistent with islet cell tumor and seminiferous tubule failure primary hypogonadism. The literature is reviewed relative to the component of this syndrome, and a possible association is discussed. The subject was investigated for a long-standing history of depression requiring medical attention because of mental confusion and slurred speech and was found to have an insulinoma. He was diagnosed with primary gonadal failure and physical examination showed no evidence of dysmorphic features. Chromosomal analysis revealed normal 46 XY and testicular biopsy showed Sertoli cell only syndrome (SCOS). Biochemistry revealed endogenous hyperinsulinism and histology confirmed an islet cell tumor. He remained euglycemic postoperatively and on followup. From this report, we emphasize drawing clinicians' attention to the possibility of an association between insulinoma and primary testicular failure and suggest consideration of this diagnosis in patients with hypergonadotropic hypogonadism who may present with infertility.

Testis cord differentiation after the sex determination stage is independent of Sox9 but fails in the combined absence of Sox9 and Sox8

Sox9 and Sox8 are transcription factors expressed in embryonic and postnatal Sertoli cells of the mouse testis. Sox9 inactivation prior to the sex determination stage leads to complete XY sex reversal. In contrast, there is normal embryonic testis development in Sox8 mutants which are initially fertile, but later develop progressive seminiferous tubule failure and infertility. To determine whether Sox9 is required for testis development after the initial steps of sex determination, we crossed Sox9 flox mice with an AMH-Cre transgenic line thereby completely deleting Sox9 in Sertoli cells by E14.0. Conditional Sox9 null mutants show normal embryonic testis development and are initially fertile, but, like Sox8 −/− mutants, become sterile from dysfunctional spermatogenesis at about 5 months. To see whether Sox8 may compensate for the absence of Sox9 during embryonic testis differentiation, we generated a Sox9 conditional knockout on a Sox8 mutant background. In the double mutants, differentiation of testis cords into seminiferous testis tubules ceases after P6 in the absence of one Sox8 allele, and after P0 in the absence of both Sox8 alleles, leading to complete primary infertility. Sox9,Sox8 double nullizygous testes show upregulation of early ovary-specific markers and downregulation of Sertoli intercellular junctions at E15.5. Their very low Amh levels still cause complete regression of the Müllerian duct but with reduced penetrance. This study shows that testis cord differentiation is independent of Sox9, and that concerted Sox9 and Sox8 function in post E14.0 Sertoli cells is essential for the maintenance of testicular function.

Sox8 and Sertoli‐cell Function

SOX8 is a transcription factor that belongs to the SoxE group of high mobility group (HMG) superfamily of genes. As Sox8 is widely expressed during development, and has male-specific expression at the critical period for sex determination, it was initially hypothesized that its inactivation would result in abnormal sex determination. Though knockout males showed normal sexual development, they did however display a progressive seminiferous tubule failure and infertility. Young males could occasionally sire litters, though fecundity decreased with age in parallel with an increase in the degeneration and disorganization of the seminiferous epithelium. SOX8 is a product of the adult Sertoli cells. Sox8 knockout males showed a progressive dysregulation of the spermatogenic cycle, including sloughing of spermatocytes and round spermatids into the epididymis and spermiation failure. Sperm that did reach the epididymis showed an age-dependent decrease in both total and progressive motility in addition to overall number. We conclude that SOX8 transactivated genes have key roles in adult Sertoli-cell function and its elimination results in progressive male infertility.

Y chromosome analysis of infertile men and their sons conceived through intracytoplasmic sperm injection: vertical transmission of deletions and rarity of de novo deletions

Objective: To determine the prevalence and type of Yq microdeletions in 86 consecutive men that fathered 99 sons by intracytoplasmic sperm injection (ICSI) and to determine the incidence of vertical transmission and de novo deletions in these boys. Design: Prospective clinical observational study. Setting: Genetics laboratory associated with a university IVF unit. Patient(s): Eighty-six consecutive infertile men presenting to an IVF clinic and their 99 ICSI-conceived sons. Fifty of the 86 men (58%) had idiopathic seminiferous tubule failure (STF); the remainder had a variety of other clinical indications for ICSI. Intervention(s): Collection of peripheral and cord blood samples. Main Outcome Measure(s): The Yq genetic status of fathers who underwent ICSI and of their sons by the presence or absence of 22 Y-specific markers covering the four azoospermia factor (AZF) subregions. Result(s): Yq deletions of the AZFd/c region were detected in two (6.9%) of 29 azoo- or severely oligospermic men with STF. Identical deletions were found in their respective sons. No de novo deletions were detected in the remaining 97 sons conceived by men without deletions. Conclusion(s): The detection of Yq deletions only in men with severe STF is consistent with previous studies, with the AZFd/c region being most commonly affected. This study demonstrates the vertical transmission of these Yq deletions through the use of ICSI and supports the notion that, in most cases, Yq deletions will be inherited by male offspring. The absence of de novo Yq deletions in the male offspring indicates that these events are rare following ICSI in men with both STF and other common male factor indications.

Male Infertility

Male infertility is a common problem; however, only approximately 25% of patients have specific or defined conditions that either make them sterile or severely infertile. About 50% of these patients have untreatable primary seminiferous tubule failure for whom donor insemination or adoption are the only possibilities of having a family. The other half have potentially treatable conditions, including genital tract obstruction, sperm autoimmunity, gonadotropin deficiency, coital disorders, or reversible toxin effects. Seventy-five percent of these patients have reduced semen quality that impairs fertility to a variable degree. So far, no treatments have been shown unequivocally to increase semen quality and fertility in this group. Assisted reproductive technology has improved the outlook for pregnancy in couples with male infertility and the new technique of intracytoplasmic sperm injection promises to further improve the outlook for those with severe sperm defects or previous failure of fertilization in vitro.

Human seminal clusterin (SP-40,40). Isolation and characterization.

Molecular cloning of the human complement inhibitor SP-40,40, has revealed strong homology to a major rat and ram Sertoli cell product, sulfated glycoprotein-2, known also as clusterin. This study reports the purification and characterization of human seminal clusterin. Two-dimensional gel electrophoresis revealed charge differences between clusterin purified from semen and the serum-derived material. Both preparations demonstrate comparable hemagglutination (clustering) activity and inhibition of C5b-6 initiated hemolysis. The average clusterin concentration in normal seminal plasma is considerably higher than that found in serum. Mean seminal plasma clusterin concentrations were significantly lower in azoospermia caused by obstruction or seminiferous tubule failure than with oligospermia or normospermia. Only men with vasal agenesis had undetectable seminal clusterin, suggesting that some of the seminal clusterin is produced by the seminal vesicles. Immunofluorescence of human spermatozoa revealed that clusterin was detected on 10% of spermatozoa, predominantly those that were immature or had abnormal morphology. A pilot study of 25 patients suggests that seminal clusterin concentration, together with sperm motility and morphology, is correlated with the fertilization rate in vitro. The function of seminal clusterin is unknown. Its extensive distribution in the male genital tract and its high concentration in seminal plasma suggests an important role in male fertility.

Different testosterone and LH relationships in infertile men.

In both man and animals, changes in Leydig cell structure and function accompany seminiferous tubule damage. In this study of 1745 men attending an infertility clinic, 14% of men with elevated levels of FSH also had elevated LH levels. Groups with severe seminiferous tubule failure (eg, Sertoli Cell Only syndrome or high FSH levels) showed an inverse correlation between LH and testosterone levels. In contrast, groups with milder forms of seminiferous tubule disorders (mild hypospermatogenesis, or FSH levels in the low-normal range) showed a positive correlation between LH and testosterone. It is concluded that different mechanisms must be operative to explain the opposite relationships between LH and testosterone, and that their elucidation may point to the etiology of some forms of seminiferous tubule damage in man.

Structural and functional abnormality of ectopic testes in rats

Some males of a mutant strain of King-Holtzman rats exhibit an anomalous heritable defect manifested as either unilateral or bilateral ectopic testes. In the adult, these testes contain seemingly immature Sertoli and Leydig cells, seminiferous tubules greatly reduced in diameter, and exhibit arrested spermatogenesis. Thus, the affected testis is essentially sterile. An inability to produce normal amounts of testosterone and androstenedione by these gonads is probably a reflection of changes that have been effected in their Leydig cells. Thus, this study suggests that abnormal function of the Leydig and Sertoli cells and seminiferous tubule failure in these mutant animals result from the physiologically cryptorchid condition.

The dissociation of the exaggerated prolactin and thyrotropin responses in seminiferous tubule failure following the administration of a double-pulse of thyrotropin-releaslng hormone

PRL and TSH secretion has been evaluated in 11 patients with seminiferous tubule failure and 9 controls. When compared to the controls, the patients had increased basal FSH, TSH and PRL levels. However, LH, E2, T and thyroid hormone levels were similar to the controls. Both groups were given two pulses of TRH (200 micrograms) at 30 min intervals. Following the initial pulse of TRH, the patients demonstrated exaggerated TSH and PRL responses. The administration of a second pulse of TRH led to a further increment of TSH secretion in the patients. There was, however, no PRL response to the second TRH pulse in either patients or controls although mean PRL levels remained significantly greater in the patients.

Gonadotropin-prolactin interrelationship in the Hre/+ rat: a longitudinal study.

To further understand the endocrine pathophysiology of seminiferous tubule failure, we have undertaken a 1-year cross-sectional study of hormonal secretion in rats which are heterozygoUs for the Hıe gene. These animals (Hre/+) develop progressive seminiferous tubular failure that has some features in common with a comparable disorder in humans. Blood samples were taken at 30, 60, 90, 120 and 360 days of age for luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (Prl) and testosterone determinations. At each time interval, the PrI response to metoclopramide, a dopaminergic antagonist, was evaluated. The gonadotropin responses to luteinizing hormone releasing hormone (LHRH) were determined at 360 days. By 30 days, FSH levels were significantly increased in Hre/+ rats and remained persistently elevated for the duration of the experiment. Castration at 1 year resulted in an increase in FSH in normal rats, but not in Hre/+ rats. In Hre/+ rats, LH levels were elevated at 90 and 120 days over those of controls, whereas testosterone concentrations were much lower. Castration at 360 days produced a significant increase in LH in both groups. Despite the decline in LH levels in Hre/+ rats to near normal at 360 days, there was still an exaggerated response of this gonadotropin to LHRH. FSH levels did not change in either group after LHRH. There were no differences in basal PrI levels in the two groups. Furthermore, both groups had a similar PrI response to metoclopramide. In both Hre/+ and normal rats, there was an age-related decline in gonadotropins and testosterone levels, whereas PrI increased. It is concluded that gonadotropin profiles are similar in rats that carry the Hre gene and humans with seminiferous tubule failure. In contrast to humans, however, the PrI response to metoclopramide is normal in Hre/+ rats

Correlation of the level of β-citryl- l-glutamic acid with spermatogenesis in rat testes

β-Citryl- l-glutamic acid, which is known to be highly concentrated in the brains of immature animals, is preferentially localized in the testes of various adult animals, including mammals, amphibians and fish, mainly in the germinal cells. In young rats, the citrylglutamate concentration increases with age and coincides with the development of late spermatocytes into early spermatids. Rats with seminiferous tubule failure induced by ductuli efferentes ligation and experimental cryptorchidism are infertile as a result of germ cell depletion, especially spermatocytes and early spermatids. In these animals, the testicular citrylglutamate content was much lower than in normal testes.

Dissociation between sleep-related and TRH-induced prolactin secretion in seminiferous tubule failure

Prolactin (PRL) secretion has been measured during sleep and following TRH administration in 8 patients aged 24–39 yr with seminiferous tubule failure and 36 controls. Basal LH levels were 25.7 ± 14.7 mIU/ml in the patients compared to 11.5 ± 4.2 mlU/ml in the controls ( p < 0.01). Corresponding FSH levels were 26.2 ± 10.7 mIU/ml and 5.9 ± 2.1 mIU/ml ( p < 0.001). Mean estradiol 17B and testosterone levels were similar in the 2 groups. The mean PRL secretion during sleep was 16.5 ± 11.7 ng/ml in the patients and not different in 11 of the controls (12.4 ± 3.2 ng/ml). One patient had a mean nocturnal PRL concentration of 44.1 ng/ml. In both groups, the mean sleep related PRL concentration was greater than that during waking hours. The average number of peaks in the 2 groups was similar. In the same patients, the peak PRL response to TRH (200 ug IV) was 81.9 ± 18.8 ng/ml as compared to 32.1 ± 10.7 ng/ml in the controls ( p < 0.001). It is concluded that PRL concentrations following pharmacological stimulation are increased in seminiferous tubule failure, whereas levels are normal in relation to the physiological stimulus of sleep.

Dissociation between sleep-related and TRH-induced prolactin secretion in seminiferous tubule failure

Dissociation between sleep-related and TRH-induced prolactin secretion in seminiferous tubule failure

Protein carboxyl-methylation in rat testes: a study of inherited and X-ray-induced seminiferous tubule failure.

Protein carboxyl-methylase (PCM), the enzyme that transfers methyl groups from S-adenosyl-methionine to free carboxyl groups on proteins, is highly localized in testes. The cellular distribution of PCM and its substrates, the methyl acceptor proteins, was investigated. Separation of testicular cells on an albumin gravity gradient revealed the preferential localization of both enzyme and substrates in spermatids. In young rats, PCM activity increases with age coincidently with germ cell maturation. Rats which are heterozygous for the Hre gene (Hre/+) are infertile as a result of germ cell depletion. In these animals, testicular PCM specific activity and total activity were, respectively, 4--6 and 40--50 times lower than in normal testes. Enzyme activity in testes from animals with x-ray-induced germ cell depletion was also very low. These observations suggest that PCM is located in germ cells.

Lipids in human testis.

The lipid composition of human testis intesticular and post-testicular causes of infertility was studied. The testicular causes of infertility was represented by patients with adult seminiferous tubule failure and Klinefelter's syndrome. The post-testicular causes of infertility were represented by patients with obstruction of efferent ducts of testes. A significant accumulation of total testicular lipids was observed in both causes of infertility. A marked increase in free and esterified cholesterol, monoglycerides and triglycerides caused the accumulation of total testicular lipids in testicular causes of infertility. The accumulation of these lipids was more pronounced in Klinefelter's syndrome compared to adult seminiferous tubule failure. In post-testicular causes of infertility, a vary marked increase in phospholipids along with cholesterol fractions and glycerides led to the accumulation of total testicular lipids. The significant increase in total phospholipids caused by the increases in phosphatidylcholine and phosphatidylethanolamine differentiates post-testicular causes of infertility from testicular causes in which phospholipid classes remained unaffected. Thus, changes in hormonal mileu due to pathological conditions also lead to marked alterations in testicular lipids.

Tests of Testicular Function

The evaluation of testicular function can be readily divided into two categories, those procedures designed to evaluate fertility and those restricted to the testing of the endocrine function of the glands. The term generally refers to the condition resulting from a deficiency of male hormone. Often hypogonadism includes or is accompanied by seminiferous-tubule failure or impairment. However, there are exceptions in which spermatogenesis appears intact despite a clinically apparent androgen deficiency. Except for functioning carcinoma of the interstitial cells of Leydig, no syndrome characterized by testicular androgen excess has been described. Endocrine Function Interest in the internal secretion of the testis was a dominant factor influencing some of the fathers of endocrinology. 1 The effects of castration and prepubertal testicular failure have been well-described. The physical findings of the androgen-deficient adult male must be included among the tests for testicular androgen secretion, for they remain the hallmark by which

Clinical disorders of the neurohypophysis.

Excerpt Diabetes insipidus is the only clinical disorder generally conceded to be of neurohypophyseal origin, but accumulating evidence suggests that the neurohypophysis may have functions now scar...

Functional Prepuberal Castration in Males1

FROM the large and heterogenous group of adults with retardation or absence of sexual development two new clinical syndromes have been recently delineated. The first, which includes the association of short stature, retarded sexual development and high urinary gonadotropin titers in women, has been described by Varney, Kenyon and Koch (1), and by Albright, Smith and Fraser (2). The second syndrome represents seminiferous tubule failure accompanied by gynecomastia and high urinary gonadotropins in men and has been described by Klinefelter, Reifenstein and Albright (3). To these two syndromes we should like to add a third which has many features in common with the syndrome described by Kenyon, but occurs in males. In essence the syndrome may be regarded as a functional prepuberal castration. The syndrome as observed by us in 6 cases was characterized by a) presence of Wolfnan duct structures in the scrotum, but absence of functional testes.